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1036

Current Organic Chemistry, 2011, 15, 1036-1057

Isolation, Biological Activities and Synthesis of Indoloquinoline Alkaloids: Cryptolepine, Isocryptolepine and Neocryptolepine
Prakash T. Parvatkara,b, Perunninakulath S. Parameswaran*,c and Santosh G. Tilve*,b
a b c

National Institute of Oceanography, Dona Paula, Goa 403 004, India Department of Chemistry, Goa University, Taleigao Plateau, Goa 403 206, India

National Institute of Oceanography, Regional Centre, Kochi 682 018, India


Abstract: The tetracyclic heteroaromatic compounds cryptolepine, isocryptolepine and neocryptolepine are all naturally occurring indoloquinoline alkaloids isolated from the shrub Cryptolepis sanguinolenta and are important due to their wide spectrum of biological properties. This review describes the isolation, brief biological activities and various synthetic methodologies developed during recent years for the preparation of this important class of alkaloids, with special emphasis on preparation and properties of cryptolepine 1, isocryptolepine 2 and neocryptolepine 3.

Keywords: Alkaloid, cryptolepine, heteroaromatic, indoloquinoline, isocryptolepine and neocryptolepine. 1. INTRODUCTION 1.1. General In recent years, indoloquinoline alkaloids have received considerable attention due to their promising DNA intercalating [1] and antimalarial properties [2-4]. According to World Health Organization (WHO), about 3.3 billion people are at risk of malaria. Every year, this leads to about 250 million malaria cases, causing nearly a million deaths, mostly of children under 5 years, justifying its classification as a dreaded infectious disease along with tuberculosis and AIDS [5]. The roots of the West African plant Cryptolepis sanguinolenta [6-19] have long been used in folk medicine for the treatment of infectious diseases, amoebiasis, fever and malaria. Since 1974, a decoction of this plant is being used in the clinical therapy of rheumatism, urinary tract infections, malaria and other diseases [20-23]. Chemical examination indicated this plant to be a rich source of several indoloquinoline alkaloids [6-19]. 1.2. Isolation So far 13 alkaloids including cryptolepine 1, isocryptolepine 2 and neocryptolepine 3 have been reported from the roots of the West African plant C. sanguinolenta (Fig. 1).
H3C N N N CH3 N N CH3

reported only in 1929 [25]. Subsequently, in 1951, Gellert et al. [6] reported this compound from the roots of C. sanguinolenta. In 1995, two research groups, i.e., Pousset et al. [10] and Sharaf et al. [26] independently reported a related alkaloid 2 and named it as isocryptolepine and cryptosanguinolentine, respectively. Isocryptolepine 2 is an angularly-fused alkaloid with indolo[3,2-c]quinoline ring system whereas cryptolepine 1 is a linearly-fused alkaloid with indolo[3,2-b]quinoline ring system. Subsequently in 1996, a new linearly-fused indolo[2,3b]quinoline alkaloid 3 was reported by two independent research groups and named it as neocryptolepine by Pieter's group [9] and cryptotackieine by Schiff's group [26]. Other alkaloids reported from the plant C. sanguinolenta include quindoline 4 [7], cryptospirolepine 5 [13], cryptolepicarboline 6 [27], cryptomisrine 7 [28], 11-isopropylcryptolepine 8 [17], cryptolepinone 9 [13-15], and bis-cryptolepine 10 [9] (Fig. 2). 1.3. Brief Biological Activities The tetracyclic heteroaromatic compounds 1 and 3 are linearly fused indoloquinolines, while compound 2 has angularly-fused ring system. All the three compounds exhibit promising antiplasmodial activity [2-4, 29] against chloroquine-resistant P. falciparum and cryptolepine has been used as a lead compound for synthetic antiplasmodial agents [30-31]. Initially, neocryptolepine was reported to show an activity comparable to cryptolepine [2-3], more recent studies have shown that, it was 7 times less active against the chloroquine-resistant P. falciparum Ghana-strain [32]. These alkaloids also intercalate with DNA double helix, causing dramatic changes in DNA conformation leading to inhibition of DNA replication and transcription [1]. The strength and mode of binding of these alkaloids to DNA have been investigated by spectroscopy and X-ray analysis [33 - 34]. Cryptolepine binds 10-fold more tightly to DNA than other alkaloids and proves to be much more cytotoxic toward B16 melanoma cells [33]. In addition, these compounds as well as some of their methyl derivatives have also shown promising antimuscarinic, antibacterial, antiviral, antimicotic, antihyperglycemic and cytotoxic properties in vitro and antitumor activity in vivo [19, 23, 35-38].
2011 Bentham Science Publishers Ltd.

1
Fig. (1).

Among these, cryptolepine 1 is a rare example of natural product whose synthesis was reported prior to its isolation from nature. It was synthesized in 1906 by Fichter and Boehringer [24] for possible use as a dye while its isolation from C. triangularis was
*Address correspondence to these authors at the Department of Chemistry, Goa University, Taleigao Plateau, Goa 403 206, India; Tel: 91-(0)-4842390814 / 832-6519317; Fax: 91-(0)-484-2390618 / 832-2452868; E-mails: param@nio.org; stilve@unigoa.ac.in
1385-2728/11 $58.00+.00

Recent Development in Indoloquinoline Alkaloids

Current Organic Chemistry, 2011, Vol. 15, No. 7 1037

CH 3 CH3 N N N H N H O N N N N CH3 N

6
CH3 N

N CH3 N H O H N N N H3C CH3 N N H CH3 N N

N N

CH 3

7
Fig. (2).

10

These alkaloids, due to their wide spectrum of biological activities, have been targets of synthetic chemists in recent years. 2. SYNTHESIS The synthetic methods used for the preparation of indoloquinoline alkaloids may be classified under the following six major categories based on the method of formation of the ring system palladium-catalyzed coupling reaction, aza-Wittig reaction, transitionmetal mediated reductive cyclization, photochemical reactions, Graebe-Ullmann reaction and other miscellaneous methods. 2.1. Palladium-catalyzed Coupling Reaction Pd-catalyzed coupling reactions [39-43] have become a powerful tool for the synthetic chemists particularly for the synthesis of biologically active natural products and for the preparation of versaPd(PPh3)4 Br + N 11 H2N 12 B(OH)2 DME, H2O

tile organic building blocks. Palladium catalysts possess a higher activity than other metal alternatives (Cu, Ni or Fe) enabling the conversion of less reactive substrates and performance at relatively low temperature. Timari et al. [44] reported the synthesis of isocryptolepine and neocryptolepine using Suzuki procedure (Schemes 1 & 2). The reaction of 3-bromoquinoline 11 with N-pivaloylaminophenyl boronic acid 12 in presence of Pd(0) catalyst afforded the desired biaryl compound 13 which, on hydrolysis with sulfuric acid gave amine 14. The compound 14 was converted to azide 15 which, on nitrene insertion, gave exclusively the indolo[3,2-c]quinoline 16. Regioselective methylation on quinoline nitrogen using dimethyl sulfate yielded the target molecule isocryptolepine 2 (Schemes 1). 3-Bromo-1H-2-quinoline 18 was prepared from 3-bromoquinoline 11 via its N-oxide 17 which, on treatment with methyl
tBuCOHN 20% H2SO4 reflux, 1d 93%

NHCOtBu NaHCO3, reflux, 4 h 90% N3

13

i) Conc. HCl, NaNO2 00C, 1h ii) NaN3, 00C, 1h 80%

1,2-dichlorobenzene

HN

N 14

N 15

1800C, 5 h 75%

N 16

Me2SO4, CH3CN reflux, 5 h

93%

N CH3 2

Scheme 1.

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Br m-CPBA N 11 CHCl3, r.t. 1d, 98% 17 B(OH)2 Br 12 NHCOtBu N O

Br

TsCl CHCl3, K2CO3 r.t., 6h, 55% N H 18

Br O

MeI DMF, 600C 3h, 81%

H2SO4, EtOH N O CH3 20 NHCOtBu reflux, 2d ~100%

19

N O Pd(PPh3)4, DME, H2O CH3 NaHCO3, 3h, 85%

POCl3, benzene O N CH3 21


Scheme 2.

NH2

reflux, 3h 65%

N N CH3 3

iodide, gave N-methyl compound 19. Coupling reaction of 19 with 12 in the presence of Pd(0) catalyst afforded the biaryl compound 20. Hydrolysis of 20 with sulfuric acid followed by cyclization using POCl3 furnished neocryptolepine 3 (Scheme 2). Fan and Ablordeppy [45] described the synthesis of 10Hindolo[3,2-b]quinoline 4 via N-arylation of 3-bromoquinoline 22 with triphenylbismuth diacetate using metallic copper, followed by oxidative cyclization of the resultant anilinoquinoline 23 using palladium acetate (Scheme 3). Arzel et al. [46] described the first halogen-dance reaction [47] in quinoline series and its application to a synthesis of quindoline (Scheme 4). Pd-catalyzed cross-coupling reaction between boronic acid 12 and 3-fluoro-2-iodoquinoline 24 using Suzuki procedure [48-51] afforded the biaryl compound 25 which, underwent cyclization on treatment with boiling pyridinium hydrochloride [52] to give quinH N N 23

doline 4 in 83% yield. The intramolecular nucleophilic displacement of fluorine with amino group is facilitated by the formation of quinoline hydrochloride. Murray et al. [53] achieved the synthesis of isocryptolepine as depicted in Scheme 5. Pd(0)-catalyzed Stille coupling reaction of 2-tributylstannyl-Nprotected indole 26 with 2-iodonitrobenzene 27 gave 2-(onitrophenyl)indole 28 which on reduction, N-formylation and Nmethylation afforded the desired formamide 29. Final ring closure was achieved by refluxing compound 29 in ethanol in presence of sulfuric acid to give isocryptolepine 2. Csanyi et al. [54] accomplished the synthesis of quindoline 4 by a regioselective coupling reaction of 2,3-dibromoquinoline [55] 30 with 12 taking into consideration the fact that the -heteroaryl halogen atom is more reactive than the -halogen atom [56] to give Npivaloyl-2-(2'-anilino)-3-bromoquinoline 31. Hydrolysis of 31 afPd(OAc)2 CF3COOH 900C, 40min. 23% N 4 H N

NH2 N 22
Scheme 3.

Ph3Bi(OAc)2 Cu, CH2Cl2 r.t., 10h, 94%

B(OH)2

Pd(PPh3)4, EtOH, toluene reflux N 25

NHCOtBu

+
N 24 I 12 H N N 4 NHCOtBu

94%

Pyridinium hydrochloride 2150C NH4OH 83%


Scheme 4.

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Current Organic Chemistry, 2011, Vol. 15, No. 7 1039

N I 27 26 R R = CH2O(CH2)2SiMe3 CH3 OHC N

SnBu3

O2N

Pd(PPh3)4 THF, reflux 98%

O2N N R 28

i) H2, Pd/C, EtOH r.t. and pressure, 98% ii) CH3COOCHO (AFA) THF, -200C, 95% iii) NaH, THF, r.t. then MeI, 96%

CH3 N EtOH H2SO4 (10%) N 2

N R
Scheme 5.

29

reflux, 50%

forded the free amine 32 which underwent cyclization when heated at 200-220C in presence of pyridinium hydrochloride to give quindoline 4 (Scheme 6). Jonckers et al. [57] described the Pd-catalyzed 'aminationarylation' approach for the synthesis of isocryptolepine (Scheme 7). This approach consists of two consecutive Pd-catalyzed reactions a selective Buchwald-Hartwig [58-63] reaction of 2chloroaniline 34 with 4-chloroquinoline 33 followed by an intramolecular arylation [64-66] of the resulting compound 35 to afford the 11H-indolo[3,2-c]quinoline 16. Hostyn et al. [67] reported the synthesis of isoneocryptolepine, a missing indoloquinoline isomer in the alkaloid series cryptolepine, neocryptolepine and isocryptolepine via two routes 1. Suzuki arylation with an intramolecular nitrene insertion (Scheme 8)
Br B(OH)2 Pd(PPh3)4 stir, r.t., 6h 54%

and 2. With a combination of a selective Buchwald-Hartwigamination with an intramolecular Heck-type reaction (Scheme 9). Suzuki reaction of 33 with 12 under Gronowitz conditions [6869] yielded compound 36 which on hydrolysis provided amine 37. Diazotization of the resulting amine 37 followed by introduction of azido group and then thermal decomposition of azide 38 in boiling o-dichlorobenzene yielded the target molecule 39 as the major product and 40 in trace amount (Scheme 8). Regioselective amination of 11 with 41 in presence of Pd(0) catalyst gave compound 42 which on Heck-type cyclization yielded predominantly 7H-indolo[2,3-c]quinoline 39 and small amount of quindoline 4. Selective N-methylation [70] of 39 using methyl iodide in refluxing toluene afforded the isoneocryptolepine 43 (Scheme 9).
Br N 31 H N N NHpiv 25% aq. H2SO4 1200C, 5.5h 85%

+
N 30 Br N 32
Scheme 6.

Br 12 NH2

NHpiv

Pyridinium hydrochloride 200-2200C, 4h aq. NH3 66% 4

Cl + N 33

NH2 Cl

Pd2(dba)3 (1 mol%), XANTPHOS (2.2 mol%) Cs2CO3, dioxane reflux, overnight, 81%

HN Cl

Pd2(dba)3 (2.5 mol%), P(tBu)3 (10 mol%) K3PO4, dioxane pressure tube 1200C, 3h, 95%

34

N 35

HN CH3I, DMF, 800C, 1 h N 16


Scheme 7.

r.t., overnight 75%

N CH3 2

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Cl B(OH)2

Pd(PPh3)4 Na2CO3, DME reflux, 20h, 96% N 36

aq. H2SO4 NHpiv EtOH NH2

+
N 33 12 NHpiv

reflux, 24h, 89% N 37

i) aq. HCl, aq. NaNO2 00C, 1.5h ii) aq. NaN3, NaOAc.3H2O 00C, 1h
Scheme 8.

N3

o-dichlorobenzene 1800C, 3h

HN NH

+
39 N 40 N 88% (trace amount)

N 38

Pd2(dba)3 Br Br H2N XANTPHOS Cs2CO3, dioxane 41 reflux, 30h, 83%

Br NH N 42

PdCl2(PPh3)2 NaOAc.3H2O DMA, 1300C, 5h

+
N 11

H N N 4 (4%)
Scheme 9.

+
N

MeI, toluene NH reflux, 2h 88% 39 (45%) N 43 CH3 N

Venkatesh et al. [71] reported the synthesis of benzimidazo[1,2a]quinoline 47 via Pd-catalyzed intramolecular heterocyclization of 2-(2-bromoanilino)quinoline 46 in which 6H-indolo[2,3-b]quinoline 48 (precursor to neocryptolepine) was formed as a minor product (Scheme 10). Miki and co-workers [72] have developed a simple approach towards isocryptolepine by applying Myers method [73-75] (Scheme 11).

Reaction of 49 with N-methyl aniline 50 in acetonitrile afforded a mixture of acids 51 and 52 respectively. The decarboxylative Heck-type cyclization of 51 was achieved using Pd(OCOCF3)2 and Ag2CO3 to give the required compound 53 in 71% yield and decarboxylated product 54 in 12% yield. The compound 53 was converted to 2 by treatment with LiAlH4 in hot dioxane.

Br m-CPBA N 44 SMe CH2Cl2, r.t. 6h, 80% N 45 SO2Me H2N 41 Br N H

sealed tube 160-1700C 6h, 75% 46

Pd(OAc)2, PPh3 N NaHCO3, DMF 1300C, 12h


Scheme 10.

+ N N H 48 (25%)

N 47 (55%)

Recent Development in Indoloquinoline Alkaloids

Current Organic Chemistry, 2011, Vol. 15, No. 7 1041

O O + N O SO2Ph 49

NHCH3 CH3CN, r.t. 0.5h 50

CH3 N + COOH

COOH N N O SO2Ph CH3

N SO2Ph

51 (73%) Pd(OCOCF3)2 Ag2CO3 5% DMSO in DMF 500C, 48 h

52 (22%)

CH3 N

O LiAlH4

CH3 N +

CH3 N

N 2
Scheme 11.

dioxane, 1 h 98%

N SO2Ph 53 (71%)

N SO2Ph 54 (12%)

Mori and Ichikawa [76] reported the synthesis of 11-alkylated cryptolepines via radical cyclization and Stille coupling reaction (Scheme 12). o-Isocyano-substituted , -difluorostyrenes 55 on treatment with tributyltin hydride in presence of catalytic amount of AIBN and subsequent Pd-catalyzed coupling reaction with 56 afforded the 2,4-disustituted-3-fluoroquinolines 57 which, on cyclization followed by methylation furnished the 11-n-butyl and 11-isopropyl cryptolepines 1b-c. 2.2. Aza-Wittig Reaction Aza-Wittig reaction [77-78] has become one of the important reactions in organic synthetic strategies directed towards the construction of acyclic and cyclic compounds as the reaction is mostly
R CF2 NC 55 n-Bu3SnH cat. AIBN toluene 800C, 1h

carried out in neutral conditions, in the absence of catalyst, generally at mild temperature and usually proceeds in high yield. Alajarin and co-workers [79] described the synthesis of neocryptolepine using aza-Wittig reaction of the iminophosphorane 59 with phenyl isocyanate 60 to yield carbodiimide 61 and triphenylphosphine oxide which, without purification, was subjected to thermal treatment to give 48 and 2-anilinoquinoline 62 in 19% and 40% yield, respectively (Scheme 13). Shi et al. [80] prepared various derivatives of 6H-indolo[2,3b]quinoline 48 using the above methodology [79] (Scheme 14). The introduction of trimethylsilyl group at the acetylenic terminus provided an efficient route to 48 by suppressing the competing pathway toward the 2-anilinoquinoline 62 as the trimethylsilyl group serve as a surrogate for the hydrogen atom in directing the
R BocHN F N 57 Pyridinium hydrochloride 1800C, 12-15h aq. NH3 66-75%

i) o-BocNHC6H4I 56 Pd(PPh3)4, CuI DMF, 800C, 4h ii) DBU, 800C, 1h 61-74% R N

H N

MeI, THF reflux, 20h 57-61%

N 58
Scheme 12.
Ph-NCO 60 N PPh3 59 toluene r.t., 15min.

N CH3 1b-c R = n-Bu, i-Pr

1600C toluene N 61 N sealed tube 10h N H 48 (19%) N + N 62 (40%) N H Ph

Scheme 13.

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+
N PPh3 59a-e OCN 60 R = H, 16% 6N NaOH (92%) R = Me3Si, 86% N H N 48a-e (76-91%)

R = H, Me3Si, Me, n-Pr, t-Bu, Ph


Scheme 14.

reaction toward the indoloquinoline. A subsequent protodesilylation using NaOH furnished 48 in good yield. Similarly, the derivatives of 48 with substitutents at C-11 position are prepared by treating the corresponding iminophosphoranes with phenyl isocyanate. Using the methodology of Alajarin et al. [79], Jonckers and coworkers [32] also prepared various cryptolepines with substituents on A-ring or D-ring and were evaluated for their cytotoxicity, antiplasmodial and antitrypanosomal activities. Molina and co-workers [81] reported the synthesis of neocryptolepine via Staudinger, aza-Wittig and electrocyclization reactions (Scheme 15). The iminophosphorane 69 was prepared by condensing 2(nitrobenzyl)triphenylphosphonium bromide 63 with 2-bromobenzaldehyde 64 in the presence of K2CO3 followed by reduction of nitro group with iron and then treatment of the resultant aminostilbene derivative 67 with triphenylphosphine dibromide 68. An aza-Wittig reaction of 69 with tosyl isocyanate 70 afforded the carbodiimide 71 which on heating underwent electrocyclic ring closure to give compound 72. Treatment of 72 with NaH in presence of CuI

and subsequent detosylation using TBAF yielded 48. Microwavepromoted methylation with DMS in DMF provided the target molecule 3. Fresneda and co-workers [82] devised a divergent synthetic approach to the alkaloids isocryptolepine and neocryptolepine which was based on the formation of key common intermediate 1-methyl(o-azidophenyl)quinoline-2-one 83 (Scheme 16). The key intermediate 83 was prepared using 63 and 2azidobenzaldehyde 74 as the starting materials which underwent Wittig reaction in presence of K2CO3 to give compound 75. Reaction of 75 with n-Bu3P followed by hydrolysis of the resultant iminophosphorane 76 and Z E isomerization of the C=C bond afforded amino-stilbene derivative 77 which, on treatment with triphosgene 78 yielded the corresponding o-vinylsubstituted isocyanate 79. Electrocyclic ring closure of 79 was achieved via microwave irradiation to give quinoline-2-one derivative 80 which, was converted to 83 by a four step sequence methylation, catalytic hydrogenation and diazotization followed by reaction with sodium azide. Selective indolization was achieved either by intramolecular

+ Br PPh3 NO2 63

K2CO3 CHO Dibenzo-18-crown-6 + Br 64 CH2Cl2, r.t. 16h, 95% NO2 65 Br

PhSH, AIBN benzene reflux 2h, 89%

Fe AcOH, EtOH NO2 66 TsNCO 70 toluene 00C to r.t. N 71 TBAF N 73


Scheme 15.

PPh3.Br2 68 benzene NH2 67 toluene Br 00C to r.t. 1h, 87% N PPh3 69 NaH, CuI N 72 Me2SO4, DMF MW N N H 48 1400C, 5 min 75% N N CH3 3 NH Ts Br diglyme, r.t. 85% Br

Br

reflux 2h, 85%

Br Ts

reflux 72%

N Ts

THF, r.t. 90%

Recent Development in Indoloquinoline Alkaloids

Current Organic Chemistry, 2011, Vol. 15, No. 7 1043

+ Br PPh3 NO 2 63

O2N CHO + N3 74 K2CO3, 18-crown-6 CH2Cl2, r.t., 16h, 85% N3 75

n-Bu3P CH 2Cl2, r.t. 5h

O 2N

i) THF, H2O, r.t., 1h 84% ii) PhSH, AIBN benzene, reflux 2h, 92% O2 N

O 2N

Triphosgene 78 CH2Cl2, 1h 00C to r.t.

O 2N

N PBu3 76 MW nitrobenzene 1500C, 12min. 80%

NH2

77

NCO 79

K2CO3, CH3I DMF

O2 N H2, Pd-C EtOH, r.t. N O 81 CH3 5h, 91%

N H

O 80

600C, 2h 82%

H2N

i) NaNO2, H2SO4, 00C, 30min.

N3 o-xylene N O 83 CH3 1500C 84

HN

N O 82 CH3

ii) aq. NaN3 r.t., 5h, 85%

O N CH3 Red-Al, toluene reflux, 32h N

Me3P, nitrobenzene MW, 1800C, 30min., 40%

N N CH3 3
Scheme 16.

N CH3 2

aza-Wittig reaction of the iminophosphorane derived from 83 and PPh3 under microwave irradiation to give neocryptolepine 3 or by nitrene-insertion process followed by reduction with Red-Al to give isocryptolepine 2. 2.3. Trasition-metal Mediated Reductive Cyclization Reductive cyclization [83] using transition metals is an effective protocol for the synthesis of compounds containing quinoline ring and thus is being used by several research groups for the synthesis of indoloquinolines. Ho and co-workers [84] reported the synthesis of cryptolepine and neocryptolepine from common intermediate 1,3-bis-(2nitrophenyl)propan-2-one 86 (Scheme 17). The key intermediate 86 was readily obtained from 2nitrophenyl acetic acid 85 by reaction with DCC in presence of DMAP. The approach to 1 involved the reduction of nitro groups with Fe powder followed by oxidative cyclization and subsequent N-methylation. On the other hand, 3 was obtained via bromination, Favorskii rearrangement of the resultant bromo compound 88 followed by reduction-cyclization using Fe powder and finally Nmethylation using methyl iodide.

Amiri-Attou et al. [85] described the synthesis of analogues of neocryptolepine via one-pot reduction-cyclization-dehydration reaction (Scheme 18). Reaction of o-nitrobenzyl chlorides 90a-e with 1-methylisatin 91 in the presence of tetrakis(dimethyl-amino)ethylene (TDAE) [86 87] afforded the corresponding -hydroxy lactams 92a-e which, on treatment with iron underwent reduction-cyclization and dehydration in one-pot to give the respective 6-methyl-6H-indolo[2,3b]quinolines 93a-e. We reported [88] the synthesis of neocryptolepine using the Perkin reaction and double reduction double cyclization as the main steps (Scheme 19). Condensation of 2-nitrobenzaldehyde 94 with 2-nitrophenyl acetic acid 85 in refluxing acetic anhydride in presence of Et3 N gave the , -unsaturated acid which on esterification afforded the required ester 95 in good yield. Reduction with Fe powder furnishes the 6H-indolo[2,3-b]quinoline 48 via double reduction-double cyclization reactions in one-pot. Sharma and Kundu [89] achieved the synthesis of neocryptolepine using indole 96 and 2- nitrobenzyl bromide 97 as the starting materials (Scheme 20).

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Fe COOH DCC, DMAP, THF NO2 85 reflux, 3h, 86% O NO2 O N 2 86 Br2, CHCl3 reflux, 1.5h, 98% MeO2C MeONa, CHCl3 NO2 00C, 20min r.t., overnight 57% Br glac. AcOH, EtOH reflux, 3.5h, 95%

H2N

N H

87 PhI(OAc)2 THF, r.t. 3h, 41% N

89

NO2

O NO2 O N 2 88

N H

4 MeI, THF reflux, 18h 72% CH3 N

Fe, glac. AcOH, EtOH reflux, 3h, 72% MeI, THF reflux, overnight 96% N CH3 N

N N H 48
Scheme 17.

N 3

TDAE R1 R2 90a-e O NO2 Cl + O DMF N CH3 91 CH3 N -200C, 1h r.t., 2h 36-87%

R1 R2

NO2

HO N 92a-e

O CH3

Fe, AcOH 1100C, 48h 33-65%


Scheme 18.

R1 R2

93a-e

a R1 = R2 = H b R1 = H, R2 = CH3 c R1 = Cl, R2 = H d R1 = R2 = OCH3 e R1, R2 = OCH2O

i) Ac2O, Et3N CHO + NO2 94 85 NO2 ii) EtOH, H SO 2 4 reflux, 24h 71% Me2SO4, CH3CN N H N 48 reflux, 6h 80% COOH reflux, 5h

NO2 COOEt NO2 95

Fe, HCl EtOH:AcOH:H2O 1200C, 24h 74%

N 3

N CH3

Scheme 19.

Recent Development in Indoloquinoline Alkaloids

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Na2CO3

+
96 N H

Br O 2N 97

CH3COCH3 : H2O 700C, 36h, 83% NO2 N H 98 N

SnCl2. 2H2O MeOH, reflux, 1h

+
N H 48 (35%) N NH2 N H 99 (27%)

100 (10%)

MeI, toluene, 1300C sealed tube, 4h, 82%

N N CH3 3
Scheme 20.

Alkylation of indole with 2-nitrobenzyl bromide 97 yielded compound 98 which, on treatment with SnCl2.2H2O afforded 48 in 35% yield along with other two compounds 99 and 100 in 27% and 10% respectively. 2.4. Photochemical Reactions Photochemical reactions [90] are valuable in organic chemistry as they proceed differently than thermal reactions and have the advantage of forming thermodynamically disfavored products by overcoming large activation barriers and allow reactivity otherwise inaccessible by thermal methods. Photochemical substrate activation often occurs without additional reagents which prevents the formation of any by-products and thus become important in the context of green chemistry. Kumar et al. [91] described the synthesis of isocryptolepine using photo-cyclization as the main step (Scheme 21).

Schiff's base 103, obtained by heating indole-3-carboxaldehyde 101 with aniline 102 in acetic acid, when irradiated at 253.7nm underwent cyclization to give 11H-indolo[3,2-c]quinoline 16 via initial photo-isomerization of the Schiff's base 103 from E- to Zisomer followed by conrotatory ring closure and subsequent oxidation by iodine. Dhanabal et al. [92] reported the synthesis of cryptolepine 1, isocryptolepine 2 and neocryptolepine 3 via heteroatom directed photoannulation technique (Schemes 22 - 24). Nucleophilic substitution of 3-bromoquinoline 11 with aniline 102 was achieved by heating at 2000C and the resultant anilinoquinoline 23 was subjected to photochemical cyclization. Interestingly, both linearly-fused and angularly-fused products 4 and 39 were obtained, which on methylation gave cryptolepine 1 and isoneocryptolepine 43 respectively (Scheme 22). Synthesis of isocryptolepine 2 and neocryptolepine 3 were obtained by photocyclization of the respective anilinoquinolines 105a

CHO + 101 N H

H2N

glac. AcOH reflux, 3 h 85%

N N H

hv, 253.7 nm, r.t. C6H6, MeOH

102

103

I2, 48h, 67%

N Me2SO4, CH3CN N H 16
Scheme 21.

CH3 N

reflux, 6 h, 83%

N 2

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Br + N 11

NH2 X

X 2000C, 5 h 72% N 23 NH

hv C6H6:MeOH:H2SO4 I2, r.t.

102 X = Cl or H Me2SO4, CH3CN reflux, 6 h 84%

NH N (51%) 39 + H N

N N 43 CH3 N N CH3

Me2SO4, CH3CN reflux, 6 h 82%

N 4 (16%)
Scheme 22.

Cl NH2 + N 104a 102 X = Cl, H, OH or OMe Me2SO4 CH3CN reflux, 6 h 83% X 72% 2000C, 5 h

HN X N 105a

hv C6H6:MeOH:H2SO4 I2, r.t., 78%

HN

N 16
Scheme 23.

N 2 CH3

NH2 X + N 104b Cl 102 X = Cl, H, OH or OMe 2000C 5h 72% N 105b X N H

hv C6H6:MeOH:H2SO4 I2, r.t., 70%

Me2SO4, CH3CN N H reflux, 6 h 80% N N

N 48
Scheme 24.

CH3 3

Recent Development in Indoloquinoline Alkaloids

Current Organic Chemistry, 2011, Vol. 15, No. 7 1047

and 105b and subsequent methylation at the quinoline nitrogen. Anilinoquinolines 105a-b were obtained from the corresponding chloroquinolines 104a-b (Schemes 23 and 24). Pitchai et al. [93] reported a simple photo-induced method for the synthesis of the methyl derivative of isocryptolepine (Scheme 25). 4-Hydroxy-2-methyl quinoline 107 was prepared by microwave irradiation of -anilinocrotonate 106 and then converted to 3-iodo4-hydroxy-2-methylquinoline 108 using a known procedure [94], which on treatment with POCl3 afforded the corresponding chlorinated compound 109. The amination reaction of 109 with aniline afforded the compound 110 which on photo irradiation and subsequent N-methylation yielded the methyl derivative of isocryptolepine. 2.5. Graebe-Ullmann Reaction Graebe-Ullmann reaction [95, 96] has been widely used for the synthesis of carbazoles as the phenyl benzotriazoles formed in the

reaction are unstable and readily undergo cyclization upon pyrolysis (catalyzed by acid) or on photolysis. Few research groups have exploited this reaction for the synthesis of indoloquinolines using haloquinolines instead of halopyridines as one of the starting materials. Peczynska-Czoch and co-workers [36] reported the synthesis of various derivatives of neocryptolepines via Graebe-Ullmann reaction (Scheme 26) and these were evaluated for their in vitro antimicrobial and cytotoxic activities. Triazoles 114a-d were prepared by heating the corresponding chloroquinolines 104a-d with benzotriazoles 113 at 110-120C. Decomposition of the triazoles 114a-d by heating at 130-180C in presence of PPA yielded the respective indoloquinolines 48a-d, which on methylation using DMS afforded the neocryptolepines 3a-d. Godlewska et al. [97] reported the synthesis of nitro-substituted 6H-indolo[2,3-b]quinolines 115 using the above methodology [36]

OH CO2C2H5 N 106 Cl POCl3 reflux, 1h 95% N 109 I CH3 MW, 3min. 80% N 107 NH2 102 EtOH, stir, r.t., 45min. 98% N HN I N CH3 CH3 I2, KI, NaOH stir, r.t., 4h 85% hv

OH I N 108 CH3

C6H6:CH3OH:H2SO4 I2, 48h, 78%

110

HN

Me2SO4, DMF MW, 3min., 82%

N 111
Scheme 25.

CH3

CH3 N CH3 112


R1

R1 N 110-1200C

+
R2 N 104a-d Cl

N N H 113 65-73% R2 N N

PPA N N 130-1800C 30-43%

114a-d Me2SO4 toluene 150-1600C 12h 40-67%

R1

R1 a R1 = R2 = H b R1 = CH3, R2 = H c R1 = CH3, R2 = 6-CH3 d R1 = CH3, R2 = 8-CH3

R2

N 48a-d

N H

R2

N CH3 3a-d

Scheme 26.

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Parvatkar et al.

and then indole nitrogen was methylated using NaH and DMS to give the corresponding analogue of neocryptolepines 116. The nitro group was reduced to the corresponding amine using SnCl2, which on treatment with p-toluenesulfonyl chloride afforded sulfonamide 118. Alkylation with (dialkylamino)alkyl chlorides and subsequent reaction with naphthylsodium yielded the 9-amino substituted neocryptolepine 121 (Scheme 27). Similarly, the 2-amino substituted
CH3 O 2N N 104e O2N CH3 Cl

neocryptolepine was prepared using 6-nitro-benzotriazole and 2chloro-4-methyl-quinoline as the starting materials. Sayed et al. [98] described the synthesis of neocryptolepines with A or D-ring substitutions using the methodology of Peczynska-Czoch and co-workers [36] and the side chain was introduced on the 2-, 3-, 8- and 9-positions using Pd-catalyzed amination reaction (Scheme 28). All these compounds were screened for in vitro
CH3 NaH, toluene Me2SO4, r.t. 1h, 97% H N TsCl N CH3 Ts N 118 N CH3 CH3

O 2N

N N H 113 SnCl2, HCl H2N CH3 N 115 N H

N 116

N CH3

reflux, 1h 52% 117 (CH2)nNR2 N Ts CH3

pyridine, r.t. N 30min, 77%

Cl(CH2)nNR2 119a-c NaOH, toluene TBAB, reflux 3h, 57-74%

NaC10H17, THF -150C, 5min

(CH2)nNR2 HN CH3

N 120a-c

N CH3

17-95%

a n=2, R=CH3 b n=3, R=CH3 c n=2, R=C2H5

N 121a-c

N CH3

Scheme 27.

R2 MeI, THF N

+
104 R1 = H, 6-Cl or 7-Cl R1 N Cl

R2 R1

N H 113 R2 = H, 5-Cl or 6-Cl

N 122

N H

reflux, 18 - 24h 30-87%

Pd(OAc)2 2-(dicyclohexylphosphanyl)biphenyl (DCPB) R2 N CH3 N NaOtBu N',N'-diethylpentane-1,4-diamine toluene, reflux, 2h (R1 = 8-Cl or 9-Cl, R2 = H) H3C 28-67% H3C H3C N NH N N CH3 124

R1 123

Pd(OAc)2 2-(di-t-butylphosphanyl)biphenyl (DTPB), NaOtBu N',N'-diethylpentane-1,4-diamine 1,4-dioxane, reflux, 2 - 24h (R1 = H, R2 = 2-Cl or 3-Cl) 55-58% H N CH3 N CH3
Scheme 28.

CH3 CH3

N 125

Recent Development in Indoloquinoline Alkaloids

Current Organic Chemistry, 2011, Vol. 15, No. 7 1049

antiplasmodial activity against a chloroquine-sensitive P. falciparum strain and for cytotoxicity on a human cell (MRC5) line. Vera-Luque et al. [99] achieved the synthesis of 6H-indolo[2,3b]quinolines via modified Graebe-Ullmann reaction under microwave irradiation (Scheme 29). Microwave irradiation of benzotriazoles 113 and 2chloroquinoline 104 afforded the respective triazoles 114a-d. The subsequent microwave irradiation of the resultant triazoles 114a-d in the presence of acid gave the respective 6H-indolo[2,3-b]quinolines 48a-d. 2.6. Other Miscellaneous Methods Cooper et al. [100] described the synthesis of quindoline utilizing the intramolecular -nucleophilic substitution as the main step (Scheme 30). Amido ketone 127 was prepared by directed lithiation of 126 followed by addition of 94, subsequent oxidation of the resultant alcohol with MnO2, reduction of nitro group using catalytic hydrogenation and N-benzoylation using benzoylchloride. The cyclized

product 128 was obtained from 127 in 80% yield by initial 1,4addition of amido anion followed by expulsion of the phenyl sulfonate. N-deprotection of 128 using NaOH in MeOH and subsequent reaction with POCl3 followed by catalytic hydrogenolysis of the resultant chlorinated compound 130 afforded quindoline 4 in good yield. Bierer and co-workers [23, 101] reported the synthesis of cryptolepine and its analogues by utilizing the procedures of Holt and Petrow [102] and Degutis and Ezerskaite [103] (Scheme 31). Reaction of substituted indolyl acetates 131 with isatin derivatives 132 gave the respective quindoline carboxylic acids 133 which were decarboxylated by heating at 2550C in Ph2O and the subsequent quindolines 4 were alkylated using the method of Fichter and Boehringer [24] to give the respective cryptolepines 1. All these compounds were evaluated for their antihyperglycemic activities in vitro and in an non-insulin-dependent diabetes mellitus (NIDDM) mouse model. Several other research groups [30, 104, 105] have reported the synthesis of cryptolepine analogues using the above methodology

R1 R2 R1 R1 N N H N + 104 N Cl MW 50 W/1800C 10 min 73-94% R2 R1

N N N N

113

R1 = H, Me or Cl

R2 = H or Me

114

H4P2O7 MW 150 W/1700C 30sec 19-54%


Scheme 29.

R1 R1

R2

N H 48

BuLi, THF, -780C O2N N 126 SO2Ph Ph N N H 128 H2, Pd/C EtOH, 95% N H OHC 94 40%

PhCOHN i) MnO2, CH2Cl2,r.t., 88% ii) H2, Pd/C, 72% iii) PhCOCl, PhNMe2 r.t., 87% N O SO2Ph 127 NaH, THF reflux, 80%

NaOH, MeOH heat, 85% O N

H N N H 129

POCl3 reflux, 95% O

N N H

130 Cl

Scheme 30.

1050 Current Organic Chemistry, 2011, Vol. 15, No. 7

Parvatkar et al.

OAc

+
N R1 131 H

H N R2 O 132 i) MeOTf ii) Na2CO3 iii) HCl 25-64%

KOH, H2O R2

N N H

R1

Ph2O 2550C, 6h

HOOC 133

N R2
Scheme 31.

R1

Cl

CH3 N+ N 1

R1

N H

R2

R1 = R2 = H R1 =H, R2= 2-F R1 = 7-Br, R2 =H R1 = 6-Cl, R2 =H R1 = H, R2 = 4-OMe

[23, 101] and were screened for their antimalarial and cytotoxic activities. Bierer and co-workers [101] have reported the synthesis of 4methoxy cryptolepine hydrochloride and a series of 11chlorocryptolepine analogues as shown below (Schemes 32 and 33) and evaluated for their antimalarial and antihyperglycemic activities. Condensation of 134 with 135 using catalytic amount of piperidine gave compound 136 as a mixture of E/Z isomers which on hydrogenation and subsequent deprotection using KOH followed
O OMe O2N

by alkylation afforded the methoxy cryptolepine hydrochloride 139 (Scheme 32). Compound 142 formed by stirring anthranilic acids 140 and bromoacetyl bromide on treatment with substituted anilines 102 provided the anthranilic acid derivatives 143. Acid-promoted cyclization of 143 with PPA gave quindolones 144 which when refluxed in POCl3 afforded the corresponding 11-chloroquindolines 145. NMethylation of 145 was achieved using methyl triflate to give the respective hydrotriflate salts which, was converted to free base and
O O2N OMe H2, Pd/C MeOH, r.t. overnight OMe CH3 N N H ii) K2CO3 iii) HCl 66% 139 N H
+

piperidine (cat.) toluene, CHCl3


0

+
N 134 Ac OMe N N Ac stir, r.t. 30 min 41% OHC 135

4A MS, stir, r.t. 1 week, 85% OMe N

N 136 Ac i) MeOTf toluene, r.t.

Cl

KOH

137
Scheme 32.

138

O COOH NH2 140 H N O R1 POCl3 reflux, 2h 10-50% R (over two steps) 1


Scheme 33.

Br 141

Br

HOOC H N O R1 142 H N R1 N H Br

NH2 R2 102 DMF, 1200C, 30h 50-90% R2 R1 = R2 = H R1 = 2-F, R2 = H R1 = 1-Cl, R2 = H R1 = 2-Cl, R2 = H R1 = H, R2 = 6-F R1 = H, R2 = 7-F R1 = H, R2 = 8-F R1 = H, R2 = 9-F R1 = H, R2 = 7-Ph

R1 HOOC

DMF/dioxane 00C, 20 min,r.t. overnight, 50-95% R2 N H

PPA 1300C, 2h

143 N N H 145 R2 i) MeOTf ii) Na2CO3 iii) HCl R1

144 CH3 Cl + N N Cl 146

R2

Cl

Recent Development in Indoloquinoline Alkaloids

Current Organic Chemistry, 2011, Vol. 15, No. 7 1051

subsequently treated with HCl to provide the corresponding 11chlorocryptolepine hydrochloride salts 146 (Scheme 33). Radl and co-workers [106] reported the synthesis of quindoline 4 via intermediate 149 by treating anthranilonitrilo derivative 147 with phenacyl bromide 148 in presence of K2CO3 (Scheme 34). Nucleophilic denitrocyclization [107] of 149 with NaH gave the required tetracyclic compound 129 which on treatment with PCl5 afforded the corresponding chloro compound 130 in 70% yield. The compound 129 may have formed by initial intramolecular 1,4addition, followed by expulsion of nitro group as nitrous acid and subsequent N-deprotection of carboethoxy group during work-up. Engqvist and Bergman [108] achieved the synthesis of neocryptolepine by simply heating the chloroindole derivative 150 with excess of N-methylaniline at reflux temperature (Scheme 35).

Sundaram et al. [109] reported the synthesis of 6H-indolo[2,3b]quinoline 48 using conjugate addition-elimination and the heterocyclization as the main steps (Scheme 36). Reaction of 151 with cyclohexanones 152 in presence of NaH underwent conjugate addition-elimination to give the corresponding adduct 153 which on heterocyclization with ammonium acetate yielded compound 154. Dethiomethylation of 154 with Ra-Ni and subsequent dehydrogenation with DDQ afforded 48. The 11sustituted 6H-indolo[2,3-b]quinolines 48c and 48e were prepared by treating compound 154 with DDQ and subsequent nickelcatalyzed cross-coupling reaction of resultant compound 156 with Grignard reagent. Dhanabal et al. [110] described the synthesis of isocryptolepine using a Fischer indole cyclization as the key step (Scheme 37).

O CN Br

K2CO3, DMF stir, r.t. 2h, 40% Cl H N

NO2 O

CO2Et N

NaH, THF stir, r.t. 1h, 90% H N N

+
147 O NHCO2Et H N 148 NO2

H2N 149 Ref. 100

PCl5, reflux 3h, 70% N

N H
Scheme 34.

129

130

R Cl

N-methylaniline (5 eq.) reflux, 0.25-2h aq. NaHCO3 250C, 1h 50-75% N

150
Scheme 35.

N H

N CH3

R = H or Me
R MeS O O153 NH4OAc, DMSO
0

MeS SMe R

NaH DMF, C6H6 r.t., 12h 81-86% R

4A MS, 120-1300C 10 - 12h 82-53% R

+
N 151 H MeS O O 152 R = H or Me R Ra - Ni EtOH, reflux 6 - 7h DDQ, dioxane reflux, 6 - 8h 86% MeS (PPh3)2NiCl2 R1MgX n-BuLi, C6H6 N N H 156 80-900C

N H DDQ, dioxane N N H 48

N N H 154

reflux, 6 - 8h N N 90-91% H R = H (40%) 155 R = Me (0%)

Me2SO 4, toluene sealed tube 150-1600C, 12h R

R1 N N N H 48c R = Me (74%) 1 48e R1 = Ph ( 82%) N CH3

3 R = H (42%) R = Me (68%)

Scheme 36.

1052 Current Organic Chemistry, 2011, Vol. 15, No. 7

Parvatkar et al.

Fischer indole reaction of 157 with 158 gave indoloquinoline 84 which exist predominantly in the hydroxy form 159 as confirmed by IR. The enol 159 when refluxed in POCl3 afforded the corresponding chloride 160 which on catalytic hydrogenation yielded isocryptolepine 2. Dutta et al. [111] developed a general method for the synthesis of various 2-substituted cryptolepines which involves regioselective thermal cyclization and reductive cyclization using triethyl phosphite as the key steps (Scheme 38). 2-Nitroacetophenone 161 underwent Vilsmeier-Haack reaction when treated with POCl3 in DMF to give the -chlorocinnamaldehyde 162 which, on treatment with excess arylamines 102a-d

in presence of 2N ethanolic HCl afforded the corresponding enaminoimine hydrochlorides 163a-d. Thermal cyclization of 163a-d at 200-250C provided the respective 2-(2-nitrophenyl)quinoline derivatives 164a-d. The quindolines 4a-d was prepared by heating 164a-d with triethyl phosphite at 160C. Portela-Cubillo et al. [112] described the microwave-mediated formal synthesis of neocryptolepine via radical intermediate (Scheme 39). The indolo-ketone 165 was treated with O-phenylhydroxylamine hydrochloride and the resultant O-phenyl oxime ether 166 was subjected to microwave irridiation in ionic liquid emimPF6 to give tetrahydroindolo[2,3-b]quinoline 155 in 69% yield.

OH + N O 157 CH3

NHNH2.HCl glac. AcOH, Conc. HCl reflux, 1350C, 5h, 65% 158

HN

N O CH3 84 N

N POCl3 N OH CH3 159


Scheme 37.

N H2, Pd/C (10%) N Cl CH3 160 70% 2

reflux, 8 h 62%

N CH3

2N ethanolic HCl POCl3, DMF NO2 CH3 161 O heat 200-2500C R .HCl R 5min. 35-41% BaO, KOH N R N 4a-d
Scheme 38.

NO2 Cl H CHO 162

H2N 102a-d

00C, 1h 800C, 4h 80%

00C, 88-92%

NO2 N R 164a-d

NO2 N H N 163a-d

P(OEt)3 reflux 4h 68-75%

acetone CH3I, reflux, 4h 65-73% N

H3C N R 1a-d R = H, CH3, Br, I

Recent Development in Indoloquinoline Alkaloids

Current Organic Chemistry, 2011, Vol. 15, No. 7 1053

PhONH 2.HCl N H pyridine, stir, r.t. 70% N H 166

t-BuPh, IL, MW 1600C, 30min. N OPh 69%

O 165

Ref. 109 N H N H N 155 N 3 N CH3

.N 167

Scheme 39.

Sayed et al. [98] reported the synthesis of aminoalkylaminosubstituted neocryptolepines using the procedure of Bergman and co-workers [113] (Scheme 40) and evaluated for their in vitro antiplasmodial activity against a chloroquine-sensitive P. falciparum strain and for cytotoxicity on a human cell line (MRC5). The key intermediate 169 was obtained via chlorination of 168 with NCS in presence of 1,4-dimethylpiperazine followed by addition of aniline which underwent cyclization when refluxed in Ph2O to give compound 129 [113] and then converted to 11-chloro-6Hindolo[2,3-b]quinolines 130 using POCl3. Methylation using methyl iodide and subsequent amination via SNAr reaction yielded the corresponding aminoalkylamino-substituted neocryptolepine derivatives. Recently, we reported [114] the synthesis of series of novel 6Hindolo[2,3-b]quinolines using iodine as a catalyst in one-pot via Schiff's base intermediate (Scheme 41).
i) N-chlorosuccinimide 1,4-dimethylpiperazine OMe CH2Cl2, 00C, 2h O

The reaction of indole-3-carboxaldehyde 101 with aryl amines 102 in presence of catalytic amount of iodine in refluxing diphenyl ether yielded indolo[2,3-b] quinolines 48 in a one-pot experiment via sequential imination, nucleophilic addition and subsequent annulation. Kraus and Guo [115] achieved a formal synthesis of neocryptolepine 3 and isocryptolepine 2 from a common intermediate 83 using an intramolecular Wittig reaction and regioselective methylation as the key steps (Scheme 42). The acid 173, prepared from isatin [116] was converted to acid chloride 174 by two different methods, one using thionyl chloride and the other using oxalyl chloride. Condensation of 2-(aminobenzyl)triphenylphosphonium bromide with 174, followed by intramolecular Wittig reaction in presence of potassium tert-butoxide at room temperature afforded lactam 177 in 62% overall yield from compound 173. Methylation of 177 gave a known intermediate 83

OMe

R Ph2O, reflux 45min - 3h 53-88% R

N H 168

N ii) trichloroacetic acid N H H 169 r.t., 2h R iii) H N R = H, 3-Cl, 4-Cl 2 102 47-56% Cl

N H 129

N H

Cl MeI, THF,reflux N H 18 - 24h 60-75% N N CH3 170 N,N'-diethylpentane1,4-diamine 133 -1550C, 1-4h 71-85% CH3 CH
3

POCl3, toluene reflux, 6 - 12h 13-79% N 130

HN

N,N'-diethylpentane-1,4-diamine 133 -1550C, 12h 56-82% CH3 CH3 CH3 N

HN

CH3

R
Scheme 40.

N H 172

N N CH3 171

1054 Current Organic Chemistry, 2011, Vol. 15, No. 7

Parvatkar et al.

CHO

NH2 I2 (10 mol%) R Ph2O, reflux, 12h 29 - 53% N H N 48 R

+
N H 101

102 R = H, 2-CH3, 3-CH3, 4-CH3, 3-Br, 2,3-benzo, 3,4-benzo

Scheme 41.

NH2 O COOH N3 173 O O N H N3Ph P 3 176 Br


+

SOCl2, C6H6 reflux, 1h or (COCl)2, CH2Cl2 r.t., 3h

O COCl N3 174 O H N 175

+ Br PPh3

CH2Cl2, r.t., 12h

t-BuOK, THF r.t., 5h 62% over 3 steps N3

MeI, K2CO3 DMF, 600C, 8h 177 98%

One step O CH3 N Ref. 82 N N 3 CH3 N N3 83


Scheme 42.

CH3

Two steps

N 2

which constitutes the formal synthesis of isocryptolepine 2 and neocryptolepine 3, respectively. 3. CONCLUSION Indoloquinoline alkaloids show remarkable biological activities and constitute important scaffolds for drug development. Due to this, synthesis of indoloquinoline alkaloids forms, one of the important fields of research in medicinal chemistry. This review presents a collection of highly interesting and useful methods for the synthesis of different types of indoloquinoline alkaloids which includes cryptolepine, isocryptolepine and neocryptolepine. Several synthetic strategies are now available which provides flexibility for introducing various substituents into the ring system. ACKNOWLEDGMENTS We thank CSIR, New Delhi for the financial support and one of us (P. T. P) thanks the CSIR, New Delhi for the award of Senior Research Fellowship. REFERENCES
[1] Molina, A.; Vaquero, J. J.; Garcia-Navio, J. L.; Alvarez-Builla, J.; de Pascual-Teresa, B.; Gago, F.; Rodrigo, M. M.; Ballesteros, M. Synthesis and DNA

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Binding Properties of -Carbolinium Derivatives and Benzologues. J. Org. Chem., 1996, 61, 5587. Cimanga, K.; De Bruyne, T.; Pieters, L.; Vlietinck, A. J.; Turger, C. A. In Vitro and in Vivo Antiplasmodial Activity of Cryptolepine and Related Alkaloids from Cryptolepis sanguinolenta. J. Nat. Prod., 1997, 60, 688. Paulo, A.; Gomes, E. T.; Steele, J.; Warhurst, D. C.; Houghton, P. J. Antiplasmodial Activity of Cryptolepis sanguinolenta Alkaloids from Leaves and Roots. Planta Med., 2000, 66, 30. Miert, S. V.; Hostyn, S.; Maes, B. U. M.; Cimanga, K.; Brun, R.; Kaiser, M.; Matyus, P.; Dommisse, R.; Lemiere, G.; Vlietinck, A.; Pieters, L. Isoneocryptolepine, a Synthetic Indoloquinoline Alkaloid, as an Antiplasmodial Lead Compound. J. Nat. Prod., 2005, 68, 674. Website of the World Health Organization : http://www.who.int/en/ (Accessed Jan. 05, 2010). Gellert, E.; Hamet, R.; Schlitter, E. Die Konstitution des Alkaloids Cryptolepin. Helv. Chim. Acta, 1951, 34, 642. Dwuma-Badu, D.; Ayim, J. S. K.; Fiagbe, N. Y. Y.; Knapp, J. E.; Schiff, P. L. Jr.; Slatkin, D. J. Constituents of West African medicinal plants XX: Quindoline from Cryptolepis sanguinolenta. J. Pharm. Sci., 1978, 67, 433. Ablordeppey, S. D.; Hufford, C. D.; Bourne, R. F.; Dwama-Badu, D. 1HNMR and 13C-NMR Assignments of Cryptolepine, A 3:4-Benz- -carboline Derivative Isolated from Cryptolepis sanguinolenta. Planta Med., 1990, 56, 416. Cimanga, K.; De Bruyne, T.; Pieters, L.; Claeys, M.; Vlietinck, A. New alkaloids from Cryptolepis sanguinolenta. Tetrahedron Lett., 1996, 37, 1703. Pousset, J.-L.; Martin, M.-T.; Jossang, A.; Bodo, B. Isocryptolepine from Cryptolepis sanguinolenta. Phytochemistry, 1995, 39, 735. Tackie, A. N.; Sharaf, M. H. M.; Schiff, P. L. Jr.; Boye, G. L.; Crouch, R. C.; Martin, G. E. Assignment of the Proton and Carbon NMR Spectra of the Indoloquinoline Alkaloid Cryptolepine. J. Heterocycl. Chem., 1991, 28, 1429. Spitzer, T. D.; Crouch, R. C.; Martin, G. E.; Sharaf, M. H. M.; Schiff, P. L. Jr.; Tackie, A. N.; Boye, G. L. Total Assignment of the Proton and Carbon NMR Spectra of the Alkaloid Quindoline-Utilization of HMQC-TOCSY to

Recent Development in Indoloquinoline Alkaloids Indirectly Establish Protonated Carbon-Protonated Carbon Connectivities. J. Heterocycl. Chem., 1991, 28, 2065. Tackie, A. N.; Boye, G. L.; Sharaf, M. H. M.; Schiff, P. L. Jr.; Crouch, R. C.; Spitzer, T. D.; Johnson, R. L.; Dunn, J.; Minick, D.; Martin, G. E. Cryptospirolepine, a Unique Spiro-nonacyclic Alkaloid Isolated from Cryptolepis sanguinolenta. J. Nat. Prod., 1993, 56, 653. Crouch, R. C.; Davis, A. O.; Spitzer, T. D.; Martin, G. E.; Sharaf, M. H. M.; Schiff, P. L. Jr.; Phoebe, C. H. Jr.; Tackie, A. N. Elucidation of the Structure of Quindolinone, a Minor Alkaloid of Cryptolepis sanguinolenta: Submiligram 1H-13C and 1H-15N Heteronuclear Shift Correlation Experiments Using Micro Inverse-Detection. J. Heterocycl. Chem., 1995, 32, 1077. Paulo, A.; Gomes, E. T.; Hougton, P. J. New Alkaloids from Cryptolepis sanguinolenta. J. Nat. Prod., 1995, 58, 1485. Fort, D. M.; Litvak, J.; Chen, J. L.; Lu, Q.; Phuan, P. W.; Cooper, R.; Bierer, D. 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Received: 04 May, 2010

Revised: 28 September, 2010

Accepted: 30 September, 2010